This invention relates to a composition and method for direct visualization of the human appendix and method, more particularly, to a composition for use in direct visualization of the human appendix and method for diagnosing appendicitis that provides direct and unambiguous visualization of the human appendix, separate and distinct from the gastrointestinal tract.
The gastrointestinal tract is a long hollow tube, or viscus, extending from the mouth to the anus, and includes the stomach, small intestine, colon, and large intestine. The gastrointestinal tract has an important and necessary physiologic function in the digestion of food into biologically usable form to sustain life.
On the other hand, unlike the gastrointestinal tract, the appendix is not a hollow tube and does not participate in any gastrointestinal function. In fact, the appendix currently has no known biologic function. Instead, the appendix is an organ, distinct from the gastrointestinal tract and not related to digestive function, that is believed to be a vestigial structure, or remnant. In anatomic descriptions, the appendix is a blind-ending pouch, 7 to 8 cm in length, connected to the cecum. The appendix contains lymphoid tissue but it is uncertain whether this serves a physiologic role in lymphoid function.
Based on these distinct anatomic and physiologic differences, the appendix is by definition not considered part of the gastrointestinal tract. These differences make it particularly challenging to visualize and detect pathology of the appendix in humans.
Computed tomography (CT scan) is an imaging technology used to obtain detailed cross-sectional imaging of the human body tissues and organs. Small and insignificant organs, such as the appendix, are amenable to visualization and detection using CT scans. During a CT scan, a rotating x-ray machine and detector assembly rotate around the patient to produce a large number of radiographic images which are in turn stored in a computer for display and archival. Controlled amounts of radiation pass through the body and are attenuated by body tissues and organs, thereby producing radiographic images.
Typical CT examinations can be performed in only a few minutes. The patient lies supine on a table and passes through a narrow tunnel called the gantry, as a rotating x-ray machine and detector assembly capture two dimensional radiographic images of the human body. Because the scan increments can be exceedingly small, on the order of a few millimeters, CT scan can be adapted for organ-specific imaging, such as the appendix. An additional benefit of the CT scan is its speed and non-invasive technology, amenable to the testing of sick, elderly, and pediatric patients, either in a hospitalized or outpatient setting.
In preparing patients for the CT examination, radiopaque materials, also known as radiodense materials, collectively termed contrast agents, can be administered orally and/or intravenously, to produce further attenuation of the x-ray beam, creating optimal image contrast. The net effect of radiopaque contrast agents is that organ and tissue contrast appear white on the radiographic image. Body organs and tissues take up intravenous contrast agents, providing a temporary window of opportunity to study physiologic functions and detailed anatomic information. Oral contrast agents fill hollow tubes, including the esophagus, stomach, and bowel, all of which are considered part of the gastrointestinal or alimentary tract, providing additional information regarding bowel function and pathology.
The speed and accuracy of CT scans are essential in the diagnosis of potentially life threatening medical conditions, including appendicitis, an inflammatory condition of the appendix. During an appendicitis event, the orifice or opening the appendix becomes obstructed due to unknown factors, presumably hypertrophy of lymphoid tissue within the appendix. A build-up of purulent collection builds up within the appendix and can perforate freely into body cavities, resulting in sepsis, which is widespread dissemination of infection throughout the body, and potential death. Purulent concretions can also calcify to form small calculi called appendicoliths.
Thus, appendicitis is a legitimate public health concern. In fact, appendicitis has a lifetime risk of between 1 in 7 and 1 in 9 persons, and over 700,000 cases are evaluated in emergency wards in the United States each year. Delayed or missed appendicitis is among the leading causes of medical liability, which involve principally the morbidity and mortality complications associated with perforation and sepsis, which can occur rapidly, without warning, proving potentially catastrophic to the patient. The perforated appendicitis risk is approximately 65% in the pediatric population, but much less in adults, possibly 1 in 500.
Appendicitis also presents an added diagnostic dilemma, and can evade timely medical diagnosis. A significant number of patients fail to show the classic clinical signs of appendicitis, such as right lower quadrant peritoneal tenderness, fever, and leukocytosis (elevated white blood cell count). In these clinical settings, CT scans can be used to significantly reduce the risk of delayed or missed appendicitis.
One of the difficulties with appendicitis diagnosis is that appendicitis is not part of the gastrointestinal tract and has no known gastrointestinal function. Appendicitis and bowel diseases do not have a common anatomic basis, form, function, or mechanism of disease. In diseases of the bowel, the bowel can become obstructed, leading to abdominal distention and changes in bowel function, such as changes frequency or consistency of bowel movements. Appendicitis produces no such early warning signs. When appendicitis occurs, it often has progressed to the point of frank perforation or peritonitis. In the common practice of performing CT examinations, there also can be a significant time lag between the imaging findings and clinical manifestations of appendicitis.
Further compounding this diagnostic dilemma is the lack of a unified medical consensus regarding the optimal technique for CT scans of the appendix, including the optimal response time between performing a CT scan and obtaining reliable diagnostic results. In actual practice, this response time can lag by as much as 4 to 6 hours or more, an unacceptable standard. Many appendicitis patients are encountered in the outpatient setting in doctor's offices and clinics, but cannot be evaluated in the typical outpatient radiology facility because of significant time limitations and the lack of an available safe diagnostic pharmaceutical agent to facilitate rapid diagnosis.
In descriptions of the prior art, indirect methods of visualizing the appendix must be distinguished from direct methods. Added distinctions also must be made regarding the contrast agent used in the indirect method of evaluation. The choice of contrast agent can be either a positive contrast agent, which appears radiopaque, or radiodense, on the CT scan image, versus a negative contrast agent, which are not radiopaque on the CT scan image. Radiodensity generally appears white on the CT scan image; whereas absence of radiodensity appears black on the CT scan image. Body organs and tissues result in variable attenuation of the x-ray beam, producing a spectrum of image contrast, from white, to gray, to black.
Diatrizoate, a radiopaque contrast agent, is designated chemically as 1-deoxy-1-(methylamino)-D-glucitol-3,5-diacetamido-2,4,6-triiodobenzoate. Gastrografin® and Gastroview® are commercially available forms of diatrizoate, dispensed in a liquid form containing a solution of diatrizoate salts, and are typically used for visualization of the gastrointestinal tract. The potential dosing possibilities of these solutions are infinite but limited by the concentration of diatrizoate salts in solution. However, the most important characteristic of diatrizoate is the high atomic weight of iodine, which allows sufficient radiodensity for visualization of surrounding tissues.
The prescribed adult dosage is 25 mL of Gastrografin® in 1500 mL of water, producing a prepared solution containing 0.6% iodine. Barium suspension is another radiopaque contrast agent and the most commonly used for CT examinations of the gastrointestinal tract. However, barium suspension is contraindicated in clinical evaluations for appendicitis because of the risk of barium-induced peritonitis when barium suspension spills freely into the peritoneal cavity. Barium suspension cannot be used as a practicable alternative contrast media when dealing with bowel perforations or indirect evaluation of the appendix.
Examples of non-radiopaque contrast agents used for CT examinations of the gastrointestinal tract include water, methylcellulose, polyethylene glycol, hydrocolloid, and perfluorocarbons.
During a routine examination of the gastrointestinal tract, the appendix is not directly visualized as it is not part of the gastrointestinal tract. However, the appendix can form an impression or indentation on the bowel during an examination, resulting in an indirect method of visualizing the appendix, which is also known as a negative contrast effect. A positive contrast effect is one in which a radiopaque contrast agent, also known as a positive contrast agent, is concentrated directly within the organ of interest.
Gastrointestinal tract examinations in the prior art can be performed for indirect visualization of the appendix using either radiopaque (positive contrast) or non-radiopaque (negative contrast) agents. However, there are no positive contrast agents available or known commercially that produce an organ-specific positive contrast effect, i.e., concentration within the appendix. An ideal diagnostic pharmaceutical agent for diagnosis of appendicitis is one which is an organ-specific positive contrast agent (radiopaque) and which concentrates within the appendix, producing a positive contrast effect.
The use of negative contrast agents in the prior art has been well studied and lead to the same conclusion: there are significant inherent technical limitations in the evaluation of appendicitis. One of the major drawbacks of negative contrast agents is that they produce a weak bowel opacification that renders the agent useless for direct visualization of the appendix. The considerable bowel distention from air and fluid associated with negative contrast agents often obscures the appendix, which is not part of the gastrointestinal tract. Consequently, the confident diagnosis of appendicitis is rendered ambiguous and not obvious. Significant clinical side effects are also problematic and include diarrhea and patient non-compliance related to bowel distention and discomfort from excessive oral fluid intake, in addition to gaseous distention produced by the addition of mannitol, sorbitol, and sugar-based flavoring agents. The work of Megibow has further shown that a negative contrast effect is not considered sufficient clinically to allow for a confident diagnosis of appendicitis.
Megibow has investigated the extensive use of negative contrast agents available in the prior art, also encompassing those described herein, and concluded that negative contrast agents are not reliable in the diagnosis of appendicitis. Even when sufficient bowel distention has been achieved, the confident diagnosis of appendicitis is not rendered unambiguous or obvious. Particularly when the appendix is surrounded by multiple distended bowel loops, containing air and fluid, the negative contrast effect can further obscure visualization of the appendix.
One of the principal reasons that indirect methods fail to provide direct or organ-specific appendiceal visualization is that the primary goal of negative contrast agents is to visualize the bowel, not the appendix. The indirect visualization of the appendix by forming an impression or indentation on distended bowel loops appears to be an incidental or secondary result or benefit. As noted above, however, the appendix is not part of the gastrointestinal tract. Consequently, appendicitis is not a disease of the gastrointestinal tract, as diseases of the gastrointestinal tract and appendicitis do not have a common origin, causative factor, or mechanism. In order for pharmaceutical agents to work effectively in the appendix, they must target the appendix by considering the distinct and defined differences in anatomy and physiologic function between the appendix and the gastrointestinal tract.
Multiple examples of indirect methods of visualizing the appendix in the prior art reinforce the shortcomings of using gastrointestinal contrast agents to achieve a negative, rather than positive, contrast effect, regardless of whether they are negative contrast agents or positive contrast agents.
In contradistinction to indirect methods of visualizing the appendix, producing a negative contrast effect, a positive contrast agent is one in which there is organ-specific concentration of a pharmaceutical agent, producing a positive contrast effect. Therefore, positive contrast agents producing a positive contrast effect are preferable and represent an ideal pharmaceutical agent.
Neutrospect is an agent in the prior art that can produce a positive contrast effect in the appendix, but the result is not organ-specific. The mechanism of action involves the intravenous administration of radiolabelled murine myoclonal antibodies, which bind to human neutrophils in vivo. The radiolabelled antibodies are sequestered and accumulated in the peri-appendiceal area during an appendicitis event, and an imaging camera detects the radioactivity in the form of a spot on the radiographic film. However, Neutrospect is not site or organ specific for appendicitis and can be associated with any type of infection.
There are a number of inherent technical and therapeutic limitations of using Neutrospect in the clinical setting. First, it is of limited value clinically because it is not organ specific and has limited specificity. Neutospect accumulates not only in the appendix but in any target organ where there is an accumulation of neutrophils, as occurs with other infections, such as inflammatory bowel disease, diverticulitis, and intra-cavitary abscesses or collections. A positive Neutospect scan can produce an accumulation of radioactivity, or a spot on the radiographic film, practically anywhere in the body where there is an infection, confounding the clinician and further rendering a diagnosis of appendicitis as ambiguous and not obvious.
In addition, significant safety issues preclude the safe administration of Neutrospect in human subjects for appendicitis diagnosis. The United States Food and Drug Administration recently suspended clinical use of Neutrospect following documented incidents of fatal anaphylactic reactions leading to cardiopulmonary demise in several hospitalized patients. The long-term implications and future of Neutrospect are presently unclear. However, these significant safety issues, in addition to limited specificity for appendicitis diagnosis, preclude Neutrospect as a practicable diagnostic pharmaceutical for clinical use, particularly in the outpatient setting.
A definite need exists for an organ-specific or purpose-limited diagnostic pharmaceutical agent for appendicitis diagnosis due to the large numbers of subjects with potential lifetime risk for developing appendicitis, estimated at between 1 in 7 and 1 in 9 persons. No such ideal pharmaceutical agent is available commercially for routine clinical application.
Because of the possibilities for large numbers of patients undergoing diagnostic evaluations for appendicitis, particularly in the outpatient setting, a further need exists for a safe diagnostic pharmaceutical agent, in addition to being organ-specific or purpose-limited for appendicitis. Also not provided in the prior art is an ideal diagnostic pharmaceutical that can be easily manufactured in read-to-use packaged individual unit doses adapted for convenient and efficient outpatient usage.
Thus, a need exists for an oral composition of diatrizoate salts which provide a sufficient and faster rate for computerized axial tomographic examinations concentrating in the appendix wherein the contrast media is concentrated in the appendix.
The prior art contains contrast agents but none like the present invention, as follows:
Patent NumberInventorIssue Date5,233,995Yudelson et al.Aug. 10, 19934,735,795Robinson et al.Apr. 05, 19885,360,604Ruddy et al.Nov. 01, 19946,424,857Henrichs et al.Jul. 23, 20026,375,931Ostensen et al.Apr. 23, 20026,409,671B1Eriksen et al.Jun. 25, 20025,716,642Bagchi et al.Feb. 10, 19984,474,747Dimo et al.Oct. 02, 19842004/0241093LauensteinDec. 02, 20045,770,181KirklandJun. 23, 19982005/0180921Taylor et al.Aug. 18, 20056,426,077Grace et al.Jul. 30, 20025,242,683KlavenessSep. 07, 19934,192,859Mackaness et al.Mar. 11, 1980